Process for the preparation of racemic citalopram diol and/or S- or R-citalopram diols and the use of such diols for the preparation of racemic citalopram, R-citalopram and/or S-citalopram

ABSTRACT

In the following, citalopram diol means 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile, as free base and/or acid addition salt. The invention relates to a process for the preparation of racemic citalopram diol and/or R- or S-citalopram diol, comprising the separation of a non-racemic mixture of R- and S-citalopram diol with more than 50% of one of the enantiomers into a fraction being enriched with S- or R-citalopram diol and a fraction comprising RS-citalopram diol wherein the ratio of R-citalopram diol:S-citalopram diol is equal to 1:1 or closer to 1:1 than in the initial mixture. The method is characterized in that (i) RS-citalopram diol is precipitated from a solution of the initial non-racemic mixture, or R- or S-citalopram diol is dissolved into a solvent from the initial non-racemic mixture, leaving a residue of RS-citalopram diol, and in that (ii) the residue/precipitate formed is separated from the final solution phase, followed by optional steps of repetition, recrystallisation, purification, isolation and conversion between free base and salts. The invention also relates to a process for the preparation of RS-citalopram, S-citalopram or R-citalopram (all as free base and/or acid addition salt) comprising the method described above followed by ring closure.

This application is a §371 national stage of International ApplicationNo. PCT/DK03/00907, filed Dec. 18, 2003, which was published in Englishas International Publication No. WO 2004/056754, and claims the benefitof U.S. Provisional Application No. 60/436,117, filed Dec. 23, 2002.

The invention relates to a process for the preparation of racemiccitalopram diol and R- or S-citalopram diol by separating an initialnon-racemic mixture of the compounds R- and S-citalopram diol (R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile)into a fraction of racemic citalopram diol and a fraction being enrichedwith S-diol or R-diol. The invention also relates to the use of suchisolated citalopram diols for the formation of the corresponding racemiccitalopram and/or S- or R-citalopram to be comprised in a pharmaceuticalcomposition.

BACKGROUND OF THE INVENTION

Citalopram is a well-known antidepressant drug that has now been on themarket for some years and has the following structure:

Citalopram may be prepared by ring closure of4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(racemic citalopram diol) as described in U.S. Pat. No. 4,650,884. Theproduct citalopram is a racemic mixture of the R- and S-enantiomers.

Further, the S-enantiomer of citalopram (escitalopram) is a valuableantidepressant of the selective serotonin reuptake inhibitor (SSRI)type. Escitalopram may be prepared by ring closure ofS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(S-diol) with retention of configuration as described in EP B1 347 066.The amount of R-citalopram compared to S-citalopram in the productescitalopram should be less than 3%.

Furthermore, a method for the preparation of a mixture of R- andS-citalopram with more than 50% of the S-enatiomer from a mixture of R-and S-diol with more than 50% of the R-diol is described in WO03000672.

It appears from the above, that products of racemic citalopram andescitalopram with the above-mentioned enantiomeric purity are requiredfor the preparation of pharmaceutical compositions and that racemiccitalopram and escitalopram products may be prepared by ring closure ofthe RS-diol and R-diol and/or S-diol. As a consequence, methods for thepreparation of products of racemic diol and S-diol being correspondinglyenantiomerically pure are required.

Processes for the preparation and purification of R- or S-diol productsare available. Such processes involve for instance enantio-selectivesynthesis as described in EP 0347066, classical resolution andchromatographic separation as described in WO03006449. Depending on thespecific process and the conditions used, the enantiomeric purity of theS-diol product may have to be improved before the S-diol product willmeet the above requirements.

Surprisingly, it has now been found that by using the process of theinvention an expensive, but apparently useless S-diol product beingcontaminated with R-diol, may easily be converted into the two valuableproducts, racemic diol and S-diol, which meet the above requirements asregards enantiomeric purity.

Furthermore, by using the process of the invention, an expensive, butapparently useless R-diol product being contaminated with S-diol, mayeasily be converted into the valuable products, racemic diol and R-diol,which meet the above requirements as regards enantiomeric purity.

More particularly, the present invention provides a process for theseparation of an initial non-racemic mixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of one of the enantiomers into a fraction beingenriched with S-diol or R-diol and a fraction comprising RS-diol,wherein the ratio of R-diol:S-diol is equal to 1:1 or closer to 1:1 thanin the initial mixture of R- and S-diol.

The process of the invention is important and very useful, in particularbecause it provides a convenient, cheap and efficient way to transform amixture of R- and S-diols which does not meet the above requirements asregards enantiomeric purity into two valuable products, RS-diol andS-diol (or R-diol), which meet the above requirements as regardsenantiomeric purity.

In another aspect, the invention provides a convenient, cheap andefficient method for making an intermediate to be used in themanufacturing of citalopram and escitalopram.

With the present invention, the process for the production of racemiccitalopram and escitalopram meeting the requirements of the respectivemarketing approvals has become more rational and more economical asregards the simplicity of the process and the utilisation of reagentsand resources.

SUMMARY OF THE INVENTION

Thus, the present invention relates to a process for the preparation ofracemic diol free base and/or acid addition salt and/or R- or S-diolfree base and/or an acid addition salt comprising a separation of aninitial non-racemic mixture of R- and S-diol free base and/or acidaddition salt with more than 50% of one of the enantiomers into afraction being enriched with S-diol or R-diol free base and/or acidaddition salt and a fraction comprising RS-diol free base and/or acidaddition salt wherein the ratio of R-diol:S-diol is equal to 1:1 orcloser to 1:1 than in the initial mixture of R- and S-diol wherein

-   -   i) RS-diol free base and/or acid addition salt is precipitated        from a solution of the initial non-racemic mixture of R- and        S-diol free base and/or acid addition salt; or        -   R- or S-diol free base and/or acid addition salt is            dissolved into a solvent from the initial non-racemic            mixture of R- and S-diol free base and/or acid addition salt            in said solvent, leaving a residue comprising RS-diol free            base and/or acid addition salt;    -   ii) the residue/precipitate formed is separated from the final        solution phase;        -   iia) if the residue/precipitate is crystalline it is            optionally recrystallised one or more times to form racemic            diol;        -   iib) if the residue/precipitate is not crystalline, steps i)            and ii) are optionally repeated until a crystalline            residue/precipitate is obtained and the crystalline            residue/precipitate is optionally recrystallised one or more            times to form racemic diol;    -   iii) the final solution phase is optionally subjected to further        purification and S-diol or R-diol free base and/or acid addition        salt is isolated from the final solution phase;    -   iv) the free bases of the diols obtained are optionally        converted to acid addition salts thereof or acid addition salts        of the diols obtained are optionally converted to other acid        addition salts or acid addition salts of the diols obtained are        optionally converted to the corresponding free bases.

Accordingly, the RS-diol free base and/or acid addition salt obtainedgives rise to the final solution phase being enriched with either the S-or R-diol free base and/or acid addition salt. The surplus of R- orS-diol free base and/or acid addition salt may then be isolated from thefinal solution phase as described below.

According to a specific embodiment, the invention relates to a processfor the preparation of racemic diol free base and/or acid addition saltusing the process described above.

According to another specific embodiment, the invention relates to aprocess for the preparation of S-diol (or R-diol) free base and/or anacid addition salt using the process described above.

According to still another specific embodiment, the invention relates tothe use of the prepared racemic diol free base and/or acid addition saltand/or S-diol (or R-diol) free base and/or an acid addition salt for thepreparation of racemic citalopram and/or S-citalopram (or R-citalopram)free base and/or acid addition salt using the process described below.

DETAILED DESCRIPTION OF THE INVENTION

Whenever used in this document, the terms “S-diol” and “S-citalopramdiol” meanS-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile.

Whenever used in this document, the terms “R-diol” and “R-citalopramdiol” meanR-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile.

Whenever used in this document, the term “RS-diol” means a mixture of R-and S-diol such as a 0.5:1.5 or 0.9:1.1 or 0.95:1.05 or 0.98:1.02 or0.99:1.01 mixture of R- and S-diol and preferably a mixture with a 1:1ratio of the R- and S-diol.

Whenever used in this document, the terms “diol enantiomer” and “diolisomer” mean either S- or R-diol.

Whenever used in this document, the term “racemic diol” means a 1:1mixture of the R- and S-diols. The term “non-racemic mixtures of diols”means mixtures which contain R- and S-diols in a ratio other than 1:1.

Whenever used in this document, the terms “citalopram enantiomer” and“citalopram isomer” mean either S- or R-citalopram.

Whenever used in this document, the term “racemic citalopram” means a1:1 mixture of R- and S-citalopram. The term “non-racemic citalopram”means mixtures which contain R- and S-citalopram in a ratio other than1:1.

As used in this description, the term “precipitation” means forming aprecipitate, in the form of crystals, an amorphous solid or an oil ormixtures thereof, from a solution of the initial non-racemic mixture ofR- and S-diol in a solvent. In the present description, a precipitatemay be an oil, an amorphous solid or crystals or mixtures thereof.

As used in this description, the term “residue” refers to the residueremaining after dissolving R- or S-diol into a solvent from an initialnon-racemic mixture of R- or S-diols. The residue may be in the form ofcrystals, an amorphous solid or an oil or mixtures thereof.

As used herein, the term “residue/precipitate” refers to either aprecipitate or a residue as defined above.

As used herein, the term “mother liquor” means the solvent remainingafter removal or separation from the precipitate.

As used herein, the term “organic and/or aqueous phase resulting fromthe selective dissolution of R- or S-diol” refers to the phase whereinR- or S-diol is dissolved from an initial non-racemic mixture of R- orS-diols.

As used herein, the term “final solution phase” refers to a motherliquor or an organic and/or aqueous phase resulting from the selectivedissolution of R- or S-diol as defined above.

As already mentioned, the above processes for the preparation ofcitalopram free base and/or acid addition salt and/or escitalopram freebase and/or acid addition salt may result in a mixture of R- andS-citalopram free base and/or acid addition salt which is not acceptablefor pharmaceutical use. According to the present invention, asurprisingly efficient process for the preparation of racemic diol andR- or S-diol free base and/or acid addition salt to be used for thepreparation of racemic citalopram free base and/or acid addition saltand R- or S-citalopram free base and/or acid addition salt has beenfound.

This new process involves the separation of an initial non-racemicmixture of R- and S-diol free base and/or acid addition salt into afraction of racemic diol free base and/or acid addition salt and afraction of R- or S-diol free base and/or acid addition salt. Thefraction of racemic diol free base and/or acid addition salt isprecipitated as an oil, an amorphous solid or in crystalline form ormixtures thereof from a solvent, and the R- or S-diol free base and/oracid addition salt is isolated from the final solution phase. Then,racemic citalopram free base and/or acid addition salt and R- orS-citalopram free base and/or acid addition salt may be formed from thecorresponding racemic diol free base and/or acid addition salt and R- orS-diol free base and/or acid addition salt by ring closure.

According to another aspect of the invention, the initial non-racemicmixture of R- and S-diol free base and/or acid addition salt isseparated into a fraction being enriched with S-diol or R-diol free baseand/or acid addition salt and a fraction comprising RS-diol free baseand/or acid addition salt wherein the ratio of R-diol:S-diol is equal to1:1 or closer to 1:1 than in the initial mixture of R- and S-diol bymixing the initial non-racemic mixture of R- and S-diol free base and/oracid addition salt with a solvent and allowing preferentially the R- orS-diol free base and/or acid addition salt to dissolve in the solventfollowed by separation of the undissolved RS-diol free base and/or acidaddition salt residue from the organic and/or aqueous phase resultingfrom the selective dissolution of R- or S-diol free base and/or acidaddition salt and isolation of R- and S-diol free base and/or acidaddition salt from said solvent.

The solvent used according to this embodiment of the invention is anysolvent which allow preferentially the R- or S-diol free base and/oracid addition salt to dissolve leaving a mixture of RS-diol free baseand/or an acid addition salt wherein the ratio of R-diol:S-diol is equalto 1:1 or closer to 1:1 than in the initial mixture of R- and S-diol asa residue. Useful solvents are solvents such as those mentioned for theprecipitation of RS-diol free base and/or RS-diol acid addition salts.

The initial non-racemic mixture of R- and S- diol free base and/or acidaddition salt used in the process of the invention may be an oil, anamorphous solid or in crystalline form; or mixtures thereof.

The residue/precipitate formed in step i) may be an oil, an amorphoussolid or in crystalline form; or a mixture thereof. Theresidue/precipitate formed in step i) is preferably in crystalline form.

According to one embodiment of the invention, the initial non-racemicmixture of R- and S-diol free base and/or acid addition salt used in theprocess of the invention contains more than 50% of S-diol, or morepreferred more than 70% of S-diol or most preferred more than 90% ofS-diol.

According to another embodiment of the invention, the initialnon-racemic mixture of R- and S-diol free base and/or acid addition saltused in the process of the invention contains less than 99.9% of S-diol,such as less than 99.5% of S-diol, or less than 99% S-diol, or less than98% of S-diol.

Accordingly, the initial non-racemic mixture of R- and S-diol free baseand/or acid addition salt may contain 50%-98% of S-diol, or 50%-99% ofS-diol, or 50%-99.5% of S-diol, or 50%-99.9% of S-diol, or 70%-98% ofS-diol, or 70%-99% of S-diol, or 70%-99.5% of S-diol, or 70%-99.9% ofS-diol, or 90%-98% of S-diol, or 90%-99% of S-diol, or 90%-99.5% ofS-diol, or 90%-99.9% of S-diol.

According to another embodiment of the invention, the initialnon-racemic mixture of R- and S-diol free base and/or acid addition saltused in the process of the invention contains more than 50% of R-diol,or more preferred more than 70% of R-iol or most preferred more than 90%of R-diol.

According to yet another embodiment of the invention, the initialnon-racemic mixture of R- and S-diol free base and/or acid addition saltused in the process of the invention contains less than 99.9% of R-diol,such as less than 99.5% of R-diol, or less than 99% R-diol, or less than98% of R-diol.

Accordingly, the initial non-racemic mixture of R- and S-diol free baseand/or acid addition salt may contain 50%-98% of R-diol, or 50%-99% ofR-diol, or 50%-99.5% of R-diol, or 50%-99.9% of R-diol, or 70%-98% ofR-diol, or 70%-99% of R-diol, or 70%-99.5% of R-diol, or 70%-99.9% ofR-diol, or 90%-98% of R-diol, or 90%-99% of R-diol, or 90%-99.5% ofR-diol, or 90%-99.9% of R-diol.

The process may be repeated until a racemic mixture of R- and S-diols isobtained and/or until the desired degree of enantiomeric purity of theR- or S-diol is obtained.

According to one embodiment of the invention, the RS-diol of theresidue/precipitate is in the form of a free base and/or an acidaddition salt; and independently thereof the R- or S-diol of the finalsolution phase is in the form of a free base and/or an acid additionsalt. Accordingly, when the RS-diol comprised in the residue/precipitateis in the form of a free base, then the R- or S-diol comprised in thefinal solution phase, may be in the form of a free base, an acidaddition salt or a mixture of a free base and an acid addition salt.Furthermore, when the RS-diol comprised in the residue/precipitate is inthe form of an acid addition salt, then the R- or S-diol comprised inthe final solution phase, may be in the form of a free base, an acidaddition salt or a mixture of a free base and acid addition salt.Finally, when the RS-diol comprised in the residue/precipitate is amixture of a free base and an acid addition salt, then the R- or S-diolcomprised in the final solution phase, may be in the form of a freebase, an acid addition salt or a mixture of a free base and acidaddition salt.

The initial non-racemic mixture of R- and S-diol used in the process ofthe invention may be present as the free base, as salts, or as a mixtureof free bases and salts.

Furthermore, the free bases of the diols obtained are optionallyconverted to acid addition salts thereof or acid addition salts of thediols obtained are optionally converted to other acid addition salts oracid addition salts of the diols obtained are optionally converted tothe corresponding free bases by methods known to those skilled in theart.

Precipitation of the RS-diol free base may be carried out by obtainingor dissolving the non-racemic mixture of R- and S-diol free base and/oracid addition salt in a suitable solvent, optionally by applying heat,and then allowing the solution to cool, or by cooling to below ambienttemperature. The precipitate is then separated from the mother liquor,preferably by filtration or decanting.

A residue of RS-diol free base may be formed by selective dissolution ofR- or S-diol free base and/or acid addition salt into a solvent from theinitial non-racemic mixture of R- and S-diols free base and/or acidaddition salt in said solvent. The residue is then separated from theorganic and/or aqueous phase resulting from the selective dissolution ofR- or S-diol.

If the residue/precipitate is crystalline, the crystals are optionallyrecrystallised one or more times to form racemic diol free base. Then,racemic citalopram free base may be formed from the racemic diol freebase by ring closure. The free base of racemic citalopram may optionallybe converted to an acid addition salt thereof, preferably thehydrobromide salt.

If the residue/precipitate formed is an oil or an amorphous solid, stepsi) and ii) may be repeated until a crystalline product is obtained. Thecrystals obtained are optionally recrystallised one or more times toform racemic diol free base. Racemic citalopram free base may be formedfrom the racemic diol free base by ring closure. The free base ofracemic citalopram is optionally converted to an acid addition saltthereof, preferably the hydrobromide salt.

The RS-diol free base prepared according to the invention is optionallyconverted to acid addition salts thereof.

An oily phase separated from the final solution phase is optionallysubjected to conventional purification processes.

The RS-diol free base prepared according to the invention may contain aminor excess of the S-diol (or R-diol). It may thus be necessary torepeat steps i) and ii) (in particular crystallisation) of the RS-diolfree base one or more times in order to obtain racemic diol. The finalsolution phases may be pooled together and the diol enantiomer containedherein may be isolated as described below.

Suitable solvents for obtaining the residue/precipitate comprising theRS-diol free base are apolar solvents for example alkanes, such asheptane or hexane, aromatic hydrocarbons such as toluene, benzene andxylene, polar solvents such as acetonitrile, alcohols such as methanoland iso-propylalcohol or ketones such as methyl isobutyl ketone; ormixtures thereof.

In a preferred embodiment, a free base of the RS-diol is obtained instep i), preferably in crystalline form.

If necessary, crystallisation may be initiated by seeding with racemiccrystalline diol free base.

The precipitation of RS-diol acid addition salt may be carried out byobtaining or dissolving the non-racemic mixture of R- and S-diol freebase or acid addition salt in a suitable solvent, if necessary byapplying heat, and adding an acid, for example as a solid, a liquid, ina solution or as a gas.

The acid used for the precipitation of a RS-diol acid addition salt isan acid which precipitates a mixture of R- and S-enantiomers and leavesthe mother liquor enriched with either the R- or S-diol enantiomer ofthe diol as the free base or an acid addition salt.

The acid used for the precipitation of a RS-diol acid addition salt maybe:

-   -   added after the initial non-racemic mixture of R- and S-diol        free base and/or acid addition salt is obtained or dissolved in        a suitable solvent; and/or    -   present in the solvent during and/or prior to dissolution of the        initial non-racemic mixture of R- and S-diol free base and/or        acid addition salt; and/or    -   present in the initial non-racemic mixture of R- and S-diol free        base and/or acid addition salt during and/or prior to        dissolution in the solvent.

A residue of RS-diol acid addition salt may be formed by selectivedissolution of R- or S-diol free base and/or acid addition salt into asolvent from the initial non-racemic mixture of R- and S-diols free baseand/or acid addition salt in said solvent, if necessary by adding anacid, for example as a solid, a liquid, in a solution or as a gas; ormixtures thereof.

The acidic part of a RS-diol acid addition salt of the residue formed instep i) is an acid, which allows the selective dissolution of either R-or S-diol free base and/or acid addition salt and leaves the undissolvedmaterial enriched with the RS-diol acid addition salt.

The acid used for forming the RS-diol acid addition salt of the residuemay be:

-   -   present in the solvent before the initial non-racemic mixture of        R- and S-diol free base and/or acid addition salt is mixed with        the solvent; and/or    -   mixed with the solvent together with the initial non-racemic        mixture of R- and S-diol free base and/or acid addition salt;        and/or    -   mixed with the solvent after the initial non-racemic mixture of        R- and S-diol free base and/or acid addition salt is mixed with        the solvent; and/or    -   present in the initial non-racemic mixture of R- and S-diol free        base and/or acid addition salt during and/or prior to the mixing        with the solvent.

Suitable acids for the formation of a residue/precipitate of RS-diolacid addition salt from an initial non-racemic mixture of R- and S-diolfree base and/or acid addition salt are inorganic acids such ashydrochloric acid, hydrobromic acid and sulphuric acid or organic acidssuch as oxalic acid, p-toluenesulfonic acid, methanesulfonic acid andacetic acid. Hydrobromic acid, hydrochloric acid and oxalic acid arepreferred acids. When these acids are used, a hydrobromide salt,hydrochloride salt or oxalate salt of the RS-diol is formed, preferablyin crystalline form. Suitably, up to 10 equivalents of acid is used.Accordingly:

-   -   0.2-10 mol of acid may be used, such as 0.2-0.4 mol, or 0.4-0.6        mol, or 0.9-1.1 mol or 1.8-2.2 mol of acid is used for each mol        of S- and R-diol comprised in the initial non-racemic mixture of        R- and S-diol free base and/or acid addition salt; and/or    -   0.3-4.0 mol, such as 0.4-0.6 mol, or 0.9-1.1 mol or 1.8-2.2 mol        of acid is used for each mol of RS-diol comprised in the        residue/precipitate.

In order to increase the ionic strength of the solution, salts such asNaCl may be added to the solution before, during or after the RS-diolacid addition salt is obtained in step i). Those skilled in the art willknow how to adjust the amount of salt added to obtain the desiredeffect.

Suitable solvents for the formation of a residue/precipitate of RS-diolacid addition salt from an initial non-racemic mixture of R- and S-diolfree base and/or acid addition salt are polar and apolar solvents suchas toluene, ethyl acetate, diethylether, THF, alcohols such asiso-propylalcohol, acetonitrile, and ketones such as acetone and methylisobutyl ketone, and water.

If the residue/precipitate formed in step i) is crystalline, thecrystals are separated from the final solution phase, preferably byfiltration or decanting. The crystals are optionally recrystallised bydissolving the crystals in a solvent, preferably by heating, andallowing the solution to cool, or by cooling to below ambienttemperature. Racemic citalopram may be formed from the crystallineracemic diol acid addition salt by ring closure. The racemic citaloprammay be converted to a pharmaceutically acceptable salt thereof,preferably the HBr salt.

If the residue/precipitate formed in step i) is not crystalline, butamorphous or an oil, or mixtures thereof, steps i) and ii) may berepeated until a crystalline product is obtained. The crystals obtainedare optionally recrystallised one or more times as described above.Racemic citalopram may be formed from the crystalline racemic diol acidaddition salt by ring closure. The racemic citalopram may be convertedinto a pharmaceutically acceptable salt thereof, preferably the HBrsalt.

An oily phase separated from the final solution phase is optionallysubjected to conventional purification processes.

Thus, the RS-diol acid addition salt prepared according to the inventionmay contain a minor excess of the S-diol (or R-diol). It may thus benecessary to repeat precipitation (in particular crystallisation) of theRS-diol acid addition salt one or more times in order to obtain aracemic mixture. The final solution phase may be pooled together and thediol enantiomer contained herein may be isolated as described below.

If necessary, crystallisation of the RS-diol acid addition salt may beinitiated by seeding with the racemic crystalline diol acid additionsalt.

The RS-diol acid addition salt prepared according to the invention isoptionally converted into other acid addition salts or the correspondingfree base.

According to a preferred embodiment of the invention, a free base of theRS-diol or a hydrochloride salt, hydrobromide salt or oxalate salt ofthe RS-diol is obtained, preferably in crystalline form in steps i),iia) and iib).

The final solution phase, extracts thereof, or a phase enriched with R-or S-diol free base and/or acid addition salt may be subjected toconventional purification processes (such as treatment with activecarbon, chromatography etc.) before evaporation of the solvent, and/orit may be subjected to one or more further precipitations of RS-diolfree base or RS-diol acid addition salt according to the invention, inorder to improve the enantiomeric purity of the diol enantiomer product.

The R- or S-diol free base and/or acid addition salt may be isolatedfrom the final solution phase using conventional procedures such asevaporation of the solvent, or in case the final solution phase isacidic by basification followed by separation of phases or by extractionof R- or S-diol free base and/or acid addition salt followed byevaporation of the solvent.

The final solution phase, extracts thereof, or a phase enriched with R-or S-diol free base and/or acid addition salt may be subjected toconventional purification processes (such as treatment with activecarbon, chromatography etc.) before the isolation from the R- or S-diolfree base and/or acid addition salts. Suitably, R- or S-diol may beprecipitated as a phosphate salt or an oxalate salt by methods known tothose skilled in the art.

It has been found that the enantiomeric purity (the ratio between thewanted isomer and the sum of both isomers) of the S- or R-diol free baseand/or acid addition salt left in the final solution phase may be ashigh as 97-98% or even higher (i.e. better) depending on the specificconditions used.

Accordingly, the S-diol (or R-diol) free base and/or acid addition saltprepared according to the invention may contain a minor amount of theR-diol (or S-diol) free base and/or acid addition salt. In oneembodiment this minor amount may be less than 3%, or more preferred lessthan 2%, or most preferred less than 1% (the ratio between the isomercontained in a minor amount and the sum of both isomers).

The R- or S-diol free base and/or acid addition salt may be purified andisolated from said solvent or final solution phase as described above.

In one embodiment, R-diol free base or acid addition salt is obtained.

In another embodiment, S-diol free base or acid addition salt isobtained.

When R- or S-diol free base is obtained, it is optionally converted toacid addition salts thereof. When R- or S-diol acid addition salt isobtained, it is optionally converted to other acid addition salts or tothe corresponding free base.

Enantiomerically-pure R- or S-diol free base and/or acid addition saltmay be mixed with a non-racemic mixture of R- and S-diol free baseand/or acid addition salt to obtain racemic diol free base and/or acidaddition salt. Racemic diol free base and/or acid addition salt may thenbe obtained by one or more precipitations of racemic diol free baseand/or an acid addition salt thereof, followed by recrystallisation asdescribed above.

R- or S-citalopram free base and/or acid addition salt may be formedfrom the corresponding R- or S-diol free base and/or acid addition saltby ring closure with retention of configuration. S-citalopram (orR-citalopram) free base and/or acid addition salt may optionally beconverted to an acid addition salt thereof, preferably the oxalate saltand optionally recrystallised.

Ring closure of the R- or S-diol free base and/or acid addition salt maybe performed via a labile ester intermediate, e.g. in the presence oftosyl-chloride, in a basic environment, as described in EP-B1-347 066.Then, the ring closing reaction proceeds with retention of thestereochemistry. R- or S-citalopram free base and/or acid addition saltof an enantiomeric purity substantially equal to the starting diol isthen obtained.

Ring closure of the obtained racemic diol free base and/or acid additionsalt may be performed in an acidic environment, as described in U.S.Pat. No. 4,650,884, or via a labile ester as described above. Thereby,racemic citalopram is obtained.

The thus-obtained enantiomerically-pure R- or S-citalopram free baseand/or acid addition salt may be mixed with a non-racemic mixture of R-and S-citalopram free base and/or acid addition salt to obtain racemiccitalopram free base and/or acid addition salt. Racemic citalopram freebase and/or acid addition salt may then be obtained by one or moreprecipitations of citalopram free base or an acid addition salt thereof,followed by recrystallisation as described above.

One particular embodiment of the invention relates to a process for thepreparation of racemic diol free base or an acid addition salt thereofand/or R- or S-diol as the free base or an acid addition salt thereof bythe separation of an initial non-racemic mixture of R- and S-diol withmore than 50% of one of the enantiomers into a fraction being enrichedwith S-diol or R-diol and a fraction consisting of RS-diol wherein theratio of R-diol:S-diol is equal to 1:1 or closer to 1:1 than in theinitial mixture of R- and S-diol wherein

-   -   i) RS-diol is precipitated from a solvent as the free base or as        an acid addition salt thereof;    -   ii) the precipitate formed is separated from the mother liquor;        -   iia) if the precipitate is crystalline it is optionally            recrystallised one or more times to form racemic diol;        -   iib) if the precipitate is not crystalline, steps i) and ii)            are optionally repeated until a crystalline precipitate is            obtained and the crystalline precipitate is optionally            recrystallised one or more times to form racemic diol;    -   iii) the mother liquor is optionally subjected to further        purification and S-diol or R-diol is isolated from the mother        liquor;    -   iv) the free bases of the diols obtained are optionally        converted to acid addition salts thereof or acid addition salts        of the diols obtained are optionally converted to other acid        addition salts or acid addition salts of the diols obtained are        optionally converted to the corresponding free bases.

Another particular embodiment of the invention relates to a process forthe preparation of racemic diol free base or an acid addition saltthereof and/or R- or S-diol as the free base or an acid addition saltthereof by the separation of an initial non-racemic mixture of R- andS-diol with more than 50% of one of the enantiomers into a fractionbeing enriched with S-diol or R-diol and a fraction consisting ofRS-diol wherein the ratio of R-diol:S-diol is equal to 1:1 or closer to1:1 than in the initial mixture of R- and S-diol wherein

-   -   i) RS-diol is precipitated from a solvent as the free base or as        an acid addition salt thereof; or        -   R- or S-diol is dissolved into a solvent from the initial            non-racemic mixture of R- or S-diols as the free base or as            an acid addition salt thereof in said solvent, leaving a            residue;    -   ii) the precipitate formed is separated from the mother liquor;        -   iia) if the precipitate is crystalline it is optionally            recrystallised one or more times to form racemic diol;        -   iib) if the precipitate is not crystalline, steps i) and ii)            are optionally repeated until a crystalline precipitate is            obtained and the crystalline precipitate is optionally            recrystallised one or more times to form racemic diol;    -   iii) the mother liquor is optionally subjected to further        purification and S-diol or R-diol is isolated from the mother        liquor;    -   iv) the free bases of the diols obtained are optionally        converted to acid addition salts thereof or acid addition salts        of the diols obtained are optionally converted to other acid        addition salts or acid addition salts of the diols obtained are        optionally converted to the corresponding free bases.

The invention is illustrated by the following examples, which may not beconstrued as limiting.

EXAMPLES

In the following examples optical purities were measured by Chiral SCFC(super critical fluid chromatography) HPLC.

Example 1 Purification of S-Diol by Precipitation of Racemic Diol as theHydrochloride Salt

General Method:

A mixture of R- and S-diols (as defined in the table below) (10 g) wasdissolved in toluene (60 mL). Aqueous hydrochloric acid solution (32 mL,1 M) was added, and in some cases solid sodium chloride was added(enough so that the concentration of NaCl in the water was approximately1 M). The mixture was stirred overnight, and filtered. The residue wasdried to give crystals of racemic diol hydrochloride, contaminated bysome S-diol hydrochloride. The mother liquor was basified with aqueousammonia solution to pH>9, and the toluene layer was separated. Theaqueous layer was washed once more with toluene, and the combinedtoluene extracts were dried over magnesium sulfate and evaporated underreduced pressure to give mainly S-diol, contaminated with a small amountof R-diol. See table for details. Recovery of material was virtuallyquantitative, with the expected partitioning of weight between therespective samples.

Before After Precipitation Precipitation Precipitate Oil afterbasification, Mixture (mixture of R separation and evaporation ofIsomers and S-diols) (enriched S-enantiomer) S % R % S % R % S % R %98.4 1.6 54 46 97.9 2.1* 95.4 4.6 55 45 98.7 1.3* 90.3 9.7 51 49 96.73.3 80 20 51 49 96.7 3.3 69 31 50 50 94.8 5.2 59 41 54 46 92 8.0*Denotes that solid NaCl was added to the mixture, sufficient so thatthe resulting water phase was approximately 1 M in NaCl.

In the following examples optical purity is measured by Chiral HPLC.

Example 2

Purification of S-Diol by Precipitation of Racemic Diol Free Base

A solution of S-diol in acetonitrile (500 mL, ca. 50-55% w/w, S:R ratio95.72:4.28) at room temperature was cooled with stirring to −14° C. Themixture was seeded with almost-racemic diol (S:R ratio ca. 60:40) afterevery drop in temperature of 2° C. After 16 hours the mixture wasfiltered, and the filter cake was dried. Analysis of the filter cakeindicated that the S:R ratio was 57.97:42.03. Analysis of the motherliquor indicated that the S:R ratio was 98.065:1.935.

Example 3

Purification of S-Diol by Precipitation of Racemic Diol Free Base

A solution of S-diol in acetonitrile (500 mL, ca. 50-55% w/w, S:R ratio95.72:4.28) at room temperature was cooled with stirring to −10° C. withcooling at a rate of 1° C./h. The mixture was seeded with almost-racemicdiol (S:R ratio ca. 60:40) after every drop in temperature of 5° C.After 40 hours at −10° C. the mixture was filtered, and the filter cakewas dried. Analysis of the filter cake indicated that the S:R ratio was59.19:40.81. Analysis of the mother liquor indicated that the S:R ratiowas 98.52:1.48.

Example 4

Purification of S-Diol by Precipitation of Racemic Diol as theHydrochloride Salt

General Method:

A mixture of R- and S-diols (as defined in the table below) (1 g) wasdissolved in toluene (10 mL). Aqueous hydrochloric acid solution (1.0equivalent; concentration as defined in the table below) was added, andsolid sodium chloride was added (enough so that the concentration ofNaCl in the water was approximately 1 or 2 M; see table below). Themixture was stirred overnight, and filtered. The residue was dried togive crystals of racemic diol hydrochloride, contaminated by some S-diolhydrochloride. The mother liquor was basified with aqueous ammoniasolution to pH>9, and the toluene layer was separated. The aqueous layerwas washed once more with toluene, and the combined toluene extractswere dried over magnesium sulfate and evaporated under reduced pressureto give mainly S-diol, contaminated with a small amount of R-diol. Seetable for details. Recovery of material was virtually quantitative, withthe expected partitioning of weight between the respective samples.

After Precipitation Oil after basification, Before separation andPrecipitation Precipitate evaporation Mixture of Aqueous Aqueous(mixture of R (enriched S- Isomers HCl NaCl and S-diols) enantiomer) S %R % Conc. (M) Conc. (M) S % R % S % R % 82.3 17.7 1.0 1.0 58.4 41.6 99.40.6 82.3 17.7 2.0 1.0 49.7 50.3 97.7 2.3 82.3 17.7 1.0 2.0 81.3 18.786.2 13.8 82.3 17.7 2.0 2.0 60.1 39.9 99.7 0.3

Example 5

Purification of S-Diol by Precipitation of Racemic Diol asP-Toluenesulfonyl, Methanesulfonyl or Acetate Salts

General Method:

A mixture of R- and S-diols (as defined in the table below) (1 g) wasdissolved in toluene or ether (10 mL; as described in the table below).Aqueous NaCl solution (1 M, 3 mL) was added. The acid (as defined in thetable below) was added neat as a liquid. The mixture was stirredovernight, and filtered or decanted. The residue was dried to give anoil or a solid. The mother liquor was basified with aqueous ammoniasolution to pH>9, and the toluene or ether layer was separated. Theaqueous layer was washed once more with toluene or ether, and thecombined organic extracts were dried over magnesium sulfate andevaporated under reduced pressure to give mainly a solid or an oil. Seetable for details. Recovery of material was virtually quantitative, withthe expected partitioning of weight between the respective samples.

After Precipitation Oil after basification, separation and BeforePrecipitation Precipitate evaporation Mixture (mixture of R (enriched S-of Isomers Acid and S-diols) enantiomer) S % R % Solvent (equiv.) S % R% S % R % 82.3 17.7 Toluene MsOH (1) 64.4 35.6 94.3 5.7 82.3 17.7Toluene MsOH (2) 48.2 51.8 90.0 10.0 82.3 17.7 Ether MsOH (1) 62.9 37.191.0 9.0 82.3 17.7 Ether MsOH (2) 55.1 44.9 89.3 10.7 82.3 17.7 TolueneAcOH (1) 71.3 28.7 96.2 3.8 82.3 17.7 Toluene AcOH (2) 65.9 34.1 94.85.2 82.3 17.7 Ether AcOH (1) 65.0 35.0 91.6 8.4 82.3 17.7 Ether AcOH (2)65.7 34.3 87.2 12.8

Example 6

Purification of S-Diol by Precipitation of a Racemic Diol Salt in theAbsence of Water

General Method:

A mixture of R- and S-diols (as defined in the table below) (1 g) wasdissolved in toluene or ether (10 mL; as described in the table below).The acid (as defined in the table below) was added neat as a solid. Themixture was stirred overnight, and filtered. The residue was dried togive an oil or a solid. Water was added to the mother liquor, and themother liquor was basified with aqueous ammonia solution to pH>9, andthe toluene or ether layer was separated. The aqueous layer was washedonce more with toluene or ether, and the combined organic extracts weredried over magnesium sulfate and evaporated under reduced pressure togive mainly a solid or an oil. See table for details. Recovery ofmaterial was virtually quantitative, with the expected partitioning ofweight between the respective samples.

After Precipitation Oil after basification, Precipitate separation andBefore Precipitation (mixture evaporation Mixture of R and (enriched S-of Isomers Acid S-diols) enantiomer) S % R % Solvent (equiv.) S % R % S% R % 82.3 17.7 Toluene TsOH (0.4) 54.9 45.1 90.9 8.1 82.3 17.7 EtherTsOH (0.4) 57.4 42.6 98.1 7.9 82.3 17.7 Toluene (CO₂H)₂ 78.4 21.6 93 7(0.2) 82.3 17.7 Toluene (CO₂H)₂ 72.1 27.8 99.97 0.03 (0.4) 82.3 17.7Toluene (CO₂H)₂ (1) 82.2 17.8 99.6 0.4 82.3 17.7 Ether (CO₂H)₂ 58.0 42.097.7 2.3 (0.2) 82.3 17.7 Ether (CO₂H)₂ 55.4 44.6 98.4 1.6 (0.4) 82.317.7 Ether (CO₂H)₂ (1) 72.0 28.0 99.5 0.5

Example 7

Purification of S-Diol by Precipitation of a Racemic Diol Salt in theAbsence of Water Using Various Solvents

General Method:

A mixture of R- and S-diols (as defined in the table below) (1 g) wasdissolved in a solvent (10 mL; as described in the table below). Theacid (as defined in the table below) was added neat as a solid. Themixture was stirred overnight, and filtered or decanted if a precipitatehad formed. Where a precipitate had formed, the residue was dried togive an oil or a solid. The mother liquor was evaporated, and theresidue was taken up in a mixture of ether and water. This mixture wasbasified with aqueous ammonia solution to pH>9, and the ether layer wasseparated. The aqueous layer was washed once more with ether, and thecombined ether extracts were dried over magnesium sulfate and evaporatedunder reduced pressure to give mainly a solid or an oil. See table fordetails. Recovery of material was virtually quantitative, with theexpected partitioning of weight between the respective samples.

After Precipitation Oil after basification, Precipitate separation andBefore Precipitation (mixture evaporation Mixture of of R and (enrichedS- Isomers Acid S-diols) enantiomer) S % R % Solvent (equiv.) S % R % S% R % 82.3 17.7 MeOH TsOH (0.4) No Precipitation 82.3 17.7 MeOH (CO₂H)₂No Precipitation (0.2) 82.3 17.7 IPA TsOH (0.4) 51.5 48.5 91.6 8.4 82.317.7 IPA (CO₂H)₂ 54.9 45.1 98.3 1.7 (0.2) 82.3 17.7 Acetonitrile TsOH(0.4) No Precipitation 82.3 17.7 Acetonitrile (CO₂H)₂ 57.2 42.8 97.2 2.8(0.2) 82.3 17.7 THF TsOH (0.4) No Precipitation 82.3 17.7 THF (CO₂H)₂53.2 46.8 98.9 1.1 (0.2) 82.3 17.7 Acetone TsOH (0.4) No Precipitation82.3 17.7 Acetone (CO₂H)₂ 56.7 43.3 98.2 1.8 (0.2) 82.3 17.7 MIBK TsOH(0.4) 56.8 43.2 98.5 1.5 82.3 17.7 MIBK (CO₂H)₂ 58.7 41.3 99.6 0.4 (0.2)

Example 8

Purification of S-diol by Precipitation of Racemic Diol Oxalate

General Method:

A mixture of R- and S-diols (as defined in the table below) (1 g) wasdissolved in toluene (10 mL). An aqueous solution of NaCl was added (1M, 3 mL) and oxalic acid (as defined in the table below) was added neatas a solid. The mixture was stirred overnight, and filtered or decantedif a precipitate had formed. Where a precipitate had formed, the residuewas dried to give an oil or a solid. The mother liquor was basified withaqueous ammonia solution to pH>9, and the toluene layer was separated.The aqueous layer was washed once more with toluene, and the combinedtoluene extracts were dried over magnesium sulfate and evaporated underreduced pressure to give mainly a solid or an oil. See table fordetails. Recovery of material was virtually quantitative, with theexpected partitioning of weight between the respective samples.

Before After Precipitation Precipitation Precipitate Oil afterbasification, Mixture of Oxalic (mixture of R separation and evaporationIsomers Acid and S-diols) (enriched S-enantiomer) S % R % (equiv.) S % R% S % R % 82.3 17.7 0.2 51.8 48.2 98.5 1.5 82.3 17.7 0.4 62.6 37.4 99.80.2 82.3 17.7 1.0 58.6 41.4 97.0 3.0 82.3 17.7 2.0 56.7 43.3 92.7 7.3

Example 9

Purification of S-Diol by Precipitation of Racemic Diol Hydrochloride inWater

General Method:

A mixture of R- and S-diols (as defined in the table below) (1 g) wasstirred with an aqueous solution of HCl (1 equivalent; see table forconcentration). The mixture was stirred overnight, and sufficient NaClwas added (as a solid) so that the concentration of NaCl was 1 M. Themixture was filtered to give a solid. To the mother liquor was addedwater and ether, was basified with aqueous ammonia solution to pH>9, andthe ether layer was separated. The aqueous layer was washed once morewith ether, and the combined ether extracts were dried over magnesiumsulfate and evaporated under reduced pressure to give mainly a solid oran oil. See table for details. Recovery of material was virtuallyquantitative, with the expected partitioning of weight between therespective samples.

After Precipitation Before Precipitation Precipitate Oil afterbasification, Mixture of (mixture of R separation and evaporationIsomers HCl and S-diols) (enriched S-enantiomer) S % R % conc. (M) S % R% S % R % 82.3 17.7 1 59.4 40.6 99.2 0.8 82.3 17.7 2 63.7 36.3 99.3 0.7

Example 10

Purification of S-Diol by Preferential Dissolution of S-DiolHydrochloride in Water

General Method:

A mixture of R- and S-diol hydrochloride salts (17.7: 82.3; 5.5 g) wasstirred with an aqueous solution of NaCl (1 M, 12 mL). The mixture wasstirred overnight, and was filtered to give a solid. To the motherliquor was added water and ether, was basified with aqueous ammoniasolution to pH>9, and the ether layer was separated. The aqueous layerwas washed once more with ether, and the combined ether extracts weredried over magnesium sulfate and evaporated under reduced pressure togive mainly a solid or an oil. The residue from filtration containedR-diol and S-diol in a ratio of 1.0:99.0. The product from work-up ofthe filtrate contained R-diol and S-diol in a ratio of 38.8:61.2.Recovery of material was virtually quantitative, with the expectedpartitioning of weight between the respective samples.

1. A process for the preparation of racemic citalopram diol(“racemic-diol”) free base or acid addition salt thereon and/or thecorresponding R- or S-diol free base or acid addition salt thereof froman initial non-racemic mixture of R- and S-diol free base or acidaddition salt thereof, comprising the steps of: i) precipitating amixture of R- and S-citalopram diol (“RS-diol”) in the form of a freebase or acid addition salt thereof from a solution of the initialnon-racemic mixture, leaving a final solution phase comprising R- orS-diol free base or acid addition salt thereof, wherein the precipitatedRS-diol comprises a ratio of R-diol:S-diol that is equal to 1:1 orcloser to 1:1 than the initial non-racemic mixture; or mixing a solutionof the initial non-racemic mixture with a solvent to preferentiallydissolve R- or S-diol free base or acid addition salt thereof into afinal solution phase, leaving a residue comprising RS-diol free base oracid addition salt thereof; ii) separating the residue/precipitate fromthe final solution phase; iii.a) if the residue/precipitate iscrystalline, optionally recrystallizing the residue/precipitate one ormore times to form racemic diol; or iii.b) if the residue/precipitate isnot crystalline, optionally repeating steps i) and ii) until acrystalline residue/precipitate is obtained and optionallyrecrystallizing the crystalline residue/precipitate one or more times toform racemic diol; iv) optionally subjecting the final solution phase tofurther purification; v) isolating S-diol or R-diol free base or acidaddition salt thereof from the final solution phase; and vi.a)optionally converting the S-diol or R-diol free base to an acid additionsalt thereof; vi.b) optionally converting the acid addition salt of theS-diol or R-diol free base to another acid addition salt; or vi.c)optionally converting the acid addition salt of the S-diol or R-diolfree base to the corresponding free base.
 2. A process for thepreparation of S-citalopram diol or citalopram diol free base or acidaddition salt thereof from an initial non-racemic mixture of R- andS-diol free base or acid addition salt thereof, comprising the steps of:i) precipitating a mixture of R- and S-citalonram diol (“RS-diol”) inthe form of a free base or acid addition salt thereof from a solution ofthe initial non-racemic mixture, leaving a final solution phase, whereinthe precipitated RS-diol comprises a ratio of R-diol: S-diol that isequal to 1:1 or closer to 1:1 than the initial non-racemic mixture; ormixing a solution of the initial non-racemic mixture with a solvent topreferentially dissolve R- or S-diol free base or acid addition saltthereof into a final solution phase, leaving a residue comprisingRS-diol free base or acid addition salt thereof; ii) separating theresidue/precipitate from the final solution phase; iii) optionallysubjecting the final solution phase to further purification; and iv)isolating S-diol or R-diol free base or acid addition salt thereof fromthe final solution phase.
 3. The process of claim 2, wherein the diolprepared is the S-diol free base or acid addition salt thereof.
 4. Theprocess of claim 2, wherein the diol prepared is the R- diol free baseor acid addition salt thereof.
 5. A process for the preparation ofracemic citalopram diol (“racemic diol”) free base or acid addition saltthereof, comprising the steps of: i) precipitating a mixture of R- andS-citalopram diol (“RS-diol”) in the form of a free base or acidaddition salt thereof from a solution of the initial non-racemicmixture, leaving a final solution phase, wherein the precipitatedRS-diol comprises a ratio of R- diol: S-diol that is equal to 1:1 orcloser to 1:1 than the initial non-racemic mixture; or mixing a solutionof the initial non-racemic mixture with a solvent to preferentiallydissolve R- or S-diol free base or acid addition salt thereof into afinal solution phase, leaving a residue comprising RS-diol free base oracid addition salt thereof; ii) separating the residue/precipitate fromthe final solution phase; iiia) if the residue/precipitate iscrystalline, optionally recrystallizing the residue/precipitate one ormore times to form racemic diol; or iiib) if the residue/precipitate isnot crystalline, optionally repeating steps i) and ii) until acrystalline residue/precipitate is obtained and optionallyrecrystallizing the crystalline residue/precipitate one or more times toform racemic diol.
 6. The process of claim 1, wherein the initialnon-racemic mixture contains more than 50% of S-diol.
 7. The process ofclaim 1, wherein the initial non-racemic mixture contains more than 50%of R-diol.
 8. The process of claim 1, wherein the ratio of R-diol:S-diolin the RS-diol of the residue/precipitate is in the range of 0.5:1.5 to1:1 .
 9. The process of claim 1, wherein the RS-diol of theresidue/precipitate and the R- or S-diol of the final solution phase areeach independently in the form of a free base or an acid addition saltthereof.
 10. The process of claim 1, wherein RS-diol free base or acidaddition salt thereof is precipitated from a solution of the initialnon-racemic mixture.
 11. The process of claim 1, wherein the RS-diol isprecipitated using an acid.
 12. The process of claim 11 wherein theinitial non-racemic mixture is obtained or dissolved in a suitablesolvent and the acid is: added after the initial non-racemic mixture isobtained or dissolved in a suitable solvent; present in the solventduring and/or prior to dissolution of the initial non-racemic mixture;and/or present in the initial non-racemic mixture during and/or prior todissolution in the solvent.
 13. The process of claim 1, wherein asolution of the initial non-racemic mixture is mixed with a solvent topreferentially dissolve R- or S-diol free base or acid addition saltthereof into a final solution phase, leaving a residue comprisingRS-diol free base or acid addition salt thereof.
 14. The process ofclaim 1, wherein RS-diol acid addition salt is formed as a residuehaving an acidic part that comprises an acid.
 15. The process of claim13 wherein the acid is: present in the solvent before the initialnon-racemic mixture is mixed with the solvent; mixed with the solventtogether with the initial non-racemic mixture; mixed with the solventafter the initial non-racemic mixture is mixed with the solvent; and/orpresent in the initial non-racemic mixture during and/or prior to themixing with the solvent.
 16. The process of claim 14, wherein theinitial non-racemic mixture is mixed with a solvent selected fromtoluene, ethylacetate, diethylether, THF, water, alcohols, acetonitrile,ketones, and mixtures thereof.
 17. The process of claim 1, wherein theresidue/precipitate is formed using an acid selected from HCl, HBr, H₂S0 ₄, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, andoxalic acid.
 18. The process of claim 17, wherein the acid is selectedfrom HCl, HBr, and oxalic acid.
 19. The process of claim 1, wherein theresidue/precipitate is formed using 0.2-10 mol of acid for each mol ofS- and R-diol comprised in the initial non-racemic mixture.
 20. Theprocess of claim 1, wherein the residue/precipitate is formed using0.3-4.0 mol of acid for each mol of RS-diol comprised in theresidue/precipitate.
 21. The process of claim 1, wherein theresidue/precipitate is RS-diol free base in crystalline form.
 22. Theprocess of claim 1, wherein the residue/precipitate is RS-diol free baseand the initial non-racemic mixture is in a solvent selected fromalkanes, aromatic hydrocarbons, polar solvents, alcohols, ketones, andmixtures thereof.
 23. The process of claim 1, wherein the final solutionphase is subjected to one or more further purifications according tosteps i) and ii) before isolation of the S-diol or R-diol free base oracid addition salt thereof from the final solution phase.
 24. Theprocess of claim 1, wherein the S-diol or R-diol free base or acidaddition salt thereof is isolated from the final solution phase byevaporation of the solvent.
 25. The process of claim 1, wherein thefinal solution phase is acidic and the S-diol or R-diol free base oracid addition salt thereof is isolated from the final solution phase bybasification of the final solution phase, followed by phase separationor extraction with a solvent, followed by evaporation of the solvent.26. The process of claim 1, wherein the S-diol or R-diol free base oracid addition salt thereof is isolated from the final solution phase byprecipitation of the R- or S-diol free base or acid addition saltthereof.
 27. The process of claim 1, wherein the S-diol or R-diol freebase or acid addition salt thereof obtained contains a minor amount ofthe opposite enantiomer.
 28. A method for the preparation of citalopramfree base or an acid addition salt thereof, and/or S-citalopram freebase or an acid addition salt thereof or R- citalopram free base or anacid addition salt thereof, comprising the process of claim 1 followedby ring closure.
 29. The process of claim 6, wherein the initialnon-racemic mixture contains more than 70% of S-diol.
 30. The process ofclaim 29, wherein the initial non-racemic mixture contains more than 90%of S-diol.
 31. The process of claim 7, wherein the initial non-racemicmixture contains more than 70% of R-diol.
 32. The process of claim 31,wherein the initial non-racemic mixture contains more than 90% ofR-diol.
 33. The process of claim 8, wherein the ratio of R-diol:S-diolin the RS-diol of the residue/precipitate is 0.5:1.5, 0.9:1.1,0.95:1.05, 0.99:1.01, 0.98:1.02, or 1:1 .
 34. The process of claim 16,wherein the solvent is selected from iso-propylalcohol, acetone, methylisobutyl ketone, and mixtures thereof.
 35. The process of claim 18,wherein a crystalline hydrobromide salt, hydrochloride salt or oxalatesalt of the RS-diol is formed.
 36. The process of claim 19, wherein theresidue/precipitate is formed using an amount of acid selected from0.2-0.4 mol, 0.4-0.6 mol, 0.9-1.1 mol, and 1.8-2.2 mol, for each mol ofS- and R-diol comprised in the initial non-racemic mixture.
 37. Theprocess of claim 20, wherein the residue/precipitate is formed using anamount of acid selected from 0.4-0.6 mol, 0.9-1.1 mol, and 1.8-2.2 molfor each mol of RS-diol comprised in the residue/precipitate.
 38. Theprocess of claim 22, wherein the solvent is selected from heptane,hexane, toluene, benzene, xylene, acetonitrile, methanol,iso-propylalcohol, methyl isobutyl ketone, and mixtures thereof.
 39. Theprocess of claim 26, wherein an S-diol or R-diol acid addition salt isprecipitated in the form of a phosphate salt or an oxalate salt.
 40. Theprocess of claim 27, wherein the S-diol or R-diol free base or acidaddition salt thereof obtained contains less than 3% of the oppositeenantiomer.
 41. The process of claim 40, wherein the S-diol or R-diolfree base or acid addition salt thereof obtained contains less than 2%of the opposite enantiomer.
 42. The process of claim 41, wherein theS-diol or R-diol free base or acid addition salt thereof obtainedcontains less than 1% of the opposite enantiomer.